Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes

Handle URI:
http://hdl.handle.net/10754/561806
Title:
Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes
Authors:
Romeo, Giuseppe F.; Materia, Luisa; Modica, Maria Nunziata; Pittal, Valeria; Salerno, Loredana; Siracusa, Maria Angela; Manetti, Fabrizio; Botta, Maurizio; Minneman, Kenneth P.
Abstract:
A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an ω-[4-(substituted phenyl)piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the α1-adrenergic receptor (α1-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α1A-, α1B-, and α1D-AR subtypes, displayed affinities in the nanomolar range. Highest affinity values were found in derivatives having a butyl connecting chain between the 4-phenylpiperidine-2,6-dione and the phenylpiperazinyl moieties. 1-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-phenylpiperidine-2,6- dione (34) showed the best affinity for the α1A-AR (pK i = 8.74) and 10-fold selectivity compared to the other two α1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α1-AR subtypes. They all blocked norepinephrine-induced stimulation of inositol phospholipid hydrolysis, thus behaving as antagonists. Binding data were used to refine a previously developed pharmacophoric model for α1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α1D-AR ligands. © 2011 Elsevier Masson SAS. All rights reserved.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Publisher:
Elsevier
Journal:
European Journal of Medicinal Chemistry
Issue Date:
Jul-2011
DOI:
10.1016/j.ejmech.2011.03.054
Type:
Article
ISSN:
02235234
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorRomeo, Giuseppe F.en
dc.contributor.authorMateria, Luisaen
dc.contributor.authorModica, Maria Nunziataen
dc.contributor.authorPittal, Valeriaen
dc.contributor.authorSalerno, Loredanaen
dc.contributor.authorSiracusa, Maria Angelaen
dc.contributor.authorManetti, Fabrizioen
dc.contributor.authorBotta, Maurizioen
dc.contributor.authorMinneman, Kenneth P.en
dc.date.accessioned2015-08-03T09:05:02Zen
dc.date.available2015-08-03T09:05:02Zen
dc.date.issued2011-07en
dc.identifier.issn02235234en
dc.identifier.doi10.1016/j.ejmech.2011.03.054en
dc.identifier.urihttp://hdl.handle.net/10754/561806en
dc.description.abstractA number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an ω-[4-(substituted phenyl)piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the α1-adrenergic receptor (α1-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α1A-, α1B-, and α1D-AR subtypes, displayed affinities in the nanomolar range. Highest affinity values were found in derivatives having a butyl connecting chain between the 4-phenylpiperidine-2,6-dione and the phenylpiperazinyl moieties. 1-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-phenylpiperidine-2,6- dione (34) showed the best affinity for the α1A-AR (pK i = 8.74) and 10-fold selectivity compared to the other two α1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α1-AR subtypes. They all blocked norepinephrine-induced stimulation of inositol phospholipid hydrolysis, thus behaving as antagonists. Binding data were used to refine a previously developed pharmacophoric model for α1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α1D-AR ligands. © 2011 Elsevier Masson SAS. All rights reserved.en
dc.publisherElsevieren
dc.subjectα1-Adrenoceptor subtypesen
dc.subject4-Phenylpiperidine-2,6-dioneen
dc.subjectLigandsen
dc.subjectPharmacophoric modelen
dc.titleNovel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypesen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalEuropean Journal of Medicinal Chemistryen
dc.contributor.institutionDipartimento di Scienze Del Farmaco, Universita di Catania, viale A. Doria 6, 95125 Catania, Italyen
dc.contributor.institutionDipartimento Farmaco Chimico Tecnologico, Universita Degli Studi di Siena, via A. Moro, 53100 Siena, Italyen
dc.contributor.institutionDepartment of Pharmacology, Emory University, 1510 Clifton Road, Atlanta, GA 30322, United Statesen
kaust.authorMinneman, Kenneth P.en
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